Trametinib, also known as GSK1120212, GSK212 or JTP74057, is conventionally named: N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-3,4,6,7-tetrahydro-6,8-dimethyl-2,4,7-trioxo-pyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl}acetamide. The formula of this compound is as the following:

Trametinib, developed by GlaxoSmithKline (GSK), is a new targeted drug for the treatment of melanoma. It is a powerful and selective MEK1/MEK2 inhibitor which can effectively prevent cancer cell proliferating and can induce cell apoptosis, and increase the life of patients. Phase III clinical trials show that the therapeutic effect of trametinib is significantly better than traditional chemotherapy drugs for treatment of advanced melanoma with BRAF V600E/K mutations and for treatment of BRAF V600E or V600K mutation-positive metastatic cutaneous melanoma. In addition, studies on therapeutic effect of Trametinib in combination with other cancer drugs is on the way and show very encouraging results. The dosage form of Trametinib include oral coating tablets, in which trametinib dimethyl sulfoxide solvate is the active ingredient (also known as GSK 1120212B). Each tablet contains 0.5 mg, 1 mg or 2 mg of Trametinib. The standard target content of dimethyl sulfoxide in Trametinib tablets is approximately 11.3 wt %(theoretical value), and the lower dimethyl sulfoxide content is approximately 9.5 wt %. Trametinib is also available in oral liquid dosage form.
Trametinib and its preparation methods were described in patent document WO2005121142A1 which discloses its 1H-NMR data. Also, WO2005121142A1 published trametinib dimethyl sulfoxide solvate. Although an example in WO2005121142A1 describes that trametinib dimethyl sulfoxide solvate can be obtained by conventional methods, neither detailed methods of the preparation, nor the stoichiometry of the trametinib dimethyl sulfoxide solvate, nor its characterization data were given except the 1H-NMR data.
The present inventors have found that trametinib dimethyl sulfoxide solvate can be obtained using the conventional methods in the field. However, the trametinib dimethyl sulfoxide solvate obtained by the conventional methods is not stable and is easy to transform its crystalline form. For example, the XRPD of the trametinib dimethyl sulfoxide solvate obtained by the conventional methods, when stored at a degree of 44% RH (relative humidity) under room temperature for a period of time (e.g., 9 months), its patterns changed, showing a form change in the solvate.
Therefore, in order to meet the strict requirements for crystalline forms of active ingredients in different pharmaceutical dosage forms, there is a need for the development of a more stable trametinib dimethyl sulfoxide solvate.